A molecular understanding of the events that underlie cognition, emotion and behavior is essential for the rational development of therapies to treat mental illness and behavioral disorders. The Abl family nonreceptor tyrosine kinases, Abl and Arg, are important for synaptic transmission and behavior in mice. Abl and Arg localize to synapses where they may contribute to activity-dependent structural rearrangements by controlling actin cytoskeletal dynamics. Although Abl family kinase activation by multiple extracellular stimuli and by Src family kinases leads to dramatic rearrangements of the actin cytoskeleton, the molecular events that lead to increased Abl and Arg kinase activity remain unclear. The aim of this proposal is to understand the cellular signaling pathways that lead to Abl family kinase activation. The first aim is to use an in vitro system to understand how Abl and Arg are activated by autophosphorylation, and to study the significance of these events on Abl and Arg activation in cultured cells. The second aim is to use in vitro approaches to establish the mechanism and specificity of Src family kinase activation of Abl and Arg. The third aim is to use cell-based assays to examine the role and specificity of Src family kinases in Abl and Arg activation by extracellular signals. By providing insights into the mechanisms that regulate Abl and Arg, these studies will enhance our understanding of how Abl and Arg function in synaptic morphology and transmission. The ultimate goal of this work is to apply a molecular understanding of learning and behavior towards the design of therapeutics for the treatment and prevention of behavioral disorders and mental illness.